Backside stimulated sensor with background current manipulation

ABSTRACT

A CMOS (Complementary Metal Oxide Semiconductor) pixel for sensing at least one selected from a biological, chemical, ionic, electrical, mechanical and magnetic stimulus. The CMOS pixel includes a substrate including a backside, a source coupled with the substrate to generate a background current, and a detection element electrically coupled to measure the background current. The stimulus, which is to be provided to the backside, affects a measurable change in the background current.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 13/950,116, filed Jul. 24, 2013, which is hereby incorporatedby reference. U.S. patent application Ser. No. 13/950,116 is itself acontinuation of U.S. patent application Ser. No. 12/853,160, filed onAug. 9, 2010, now U.S. Pat. No. 8,519,490, also hereby incorporated byreference.

BACKGROUND

1. Technical Field

Embodiments of affinity based sensors are disclosed herein. Inparticular, but not exclusively, embodiments of backside stimulated CMOS(Complementary Metal Oxide Semiconductor) type sensors are disclosedherein. In embodiments, the sensors utilize their background current tomeasure affinity related stimuli to their backside surfaces.

2. Background Information

Affinity based detection is a fundamental method of identification andmeasurement. For example, affinity based detection may be used toidentify and measure the abundance of biological and biochemicalanalytes. It is an important analytical method in many fields ofendeavor including biotechnology. Affinity based biosensors utilizeselective interaction and binding of a target analyte with immobilizedcapturing probes to specifically capture the target analyte onto a solidsurface. Such specific capturing generates detectable signals based onthe captured analytes. The generated signals correlate with the presenceof target analytes, e.g., ions, toxins, polymers, hormones, DNA strands,protein, cells, etc., and hence are used to estimate the analytes'abundance.

To create the target-specific signals, the target analytes in a samplefirst collide with a capturing layer that is equipped with probes, bindto the probes, and initiate a transduction process, i.e., a process thatproduces measurable signals, e.g., electrical, mechanical or opticalsignals, that are produced solely by the captured entities. The signalsare then processed by various means, for example, semiconductor basedsignal processing techniques.

Various affinity based sensors are known in the arts. However, there isa general need in the art for new and useful affinity based sensors.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The invention may best be understood by referring to the followingdescription and accompanying drawings that are used to illustrateembodiments of the invention. In the drawings:

FIG. 1 is a cross sectional view of a CMOS biosensor system showingbio-probes on the backside surface.

FIG. 2A is a cross sectional view of a CMOS biosensor backside surfaceshowing positive ions binding to the backside surface.

FIG. 2B is a cross sectional view of a CMOS biosensor backside surfaceshowing negative ions binding to the backside surface,

FIG. 2C is a cross sectional view of a CMOS biosensor backside surfaceshowing heparin molecules binding to protamine bio-receptors on thebackside surface.

FIG. 2D is a cross sectional view of a CMOS biosensor backside surfaceshowing target DNA binding to probe DNA bio-probes on the backsidesurface.

FIG. 2E is a cross sectional view of a CMOS biosensor backside surfaceshowing target antigen binding to antigen bio-probes on the backsidesurface.

FIG. 2F is a cross sectional view of a CMOS biosensor backside surfaceshowing analyte binding to enzyme bio-probes on the backside surface.

FIG. 2G is a cross sectional view of a CMOS biosensor backside surfaceshowing analyte stimulating a cellular bio-probe on the backsidesurface.

FIG. 2H is a cross sectional view of a CMOS biosensor backside surfaceshowing analyte stimulating a tissue bio-probe on the backside surface.

FIG. 3A is a perspective sectional view of a CMOS pixel that contains adiode and STI structure, without manipulation to the diode or the STIstructure.

FIG. 3B is a perspective sectional view of a CMOS pixel that contains adiode that has been manipulated to possess a different geometric shapefrom an unmanipulated diode.

FIG. 3C is a cross sectional view of a CMOS pixel that contains an STIstructure that has been manipulated to possess a surface that is rougherthan that of an unmanipulated STI structure.

FIG. 3D is a cross sectional view of a CMOS pixel that has beenmanipulated to contain dopant that affects the background current of theCMOS pixel.

FIG. 3E is a cross sectional view of a CMOS pixel in the vicinity of aninductive element or member that alters the temperature of the CMOSpixel, thereby affecting the background current of the CMOS pixel.

FIG. 3F is a cross sectional view of a CMOS pixel in the vicinity of ainductive element or member, a temperature sensor, and a referencepixel, forming a feedback mechanism that controls the temperature of theCMOS pixel, thereby affecting the background current of the CMOS pixel.

FIG. 4A is a cross sectional view of a CMOS pixel array that detects themovement of charged entities at or near the backside surface.

FIG. 4B is a cross sectional view of a modified backside surface of aCMOS pixel array where bump structures form channels that facilitatesthe detection of the movement of charged entities.

FIG. 5 is a cross sectional view of a CMOS biosensor system thatcontains a cantilever structure on its backside surface.

FIG. 6A is a cross sectional view of the backside surface a CMOSbiosensor pixel that includes a cantilever structure that couples to thebackside surface through a block type structure.

FIG. 6B is a cross sectional view of the backside surface a CMOSbiosensor pixel that includes a cantilever structure that couples to thebackside surface through a tip type structure.

FIG. 6C is a cross sectional view of the backside surface a CMOSbiosensor pixel that includes a cantilever structure that issubstantially situated on the backside surface.

FIG. 7 is a block diagram illustrating a CMOS biosensor, in accordancewith an embodiment.

FIG. 8 is a circuit diagram illustrating sample pixel circuitry of twoCMOS biosensor pixels within a biosensor array, in accordance with anembodiment.

FIG. 9 is a cross sectional view of a CMOS ion sensor system with areference electrode proximate to its backside surface, in accordancewith an embodiment.

FIG. 10 is a cross sectional view of a CMOS ion sensor system having areference electrode structure on its backside surface, in accordancewith an embodiment.

FIG. 11 is a cross sectional view of a CMOS ion sensor system having areference electrode structure opposite its backside surface, inaccordance with an embodiment.

DETAILED DESCRIPTION

In the following description, numerous specific details are set forth.However, it is understood that embodiments of the invention may bepracticed without these specific details. In other instances, well-knowncircuits, structures and techniques have not been shown in detail inorder not to obscure the understanding of this description.

Throughout this specification, several terms of art are used. Theseterms are to take on their ordinary meaning in the art from which theycome, unless specifically defined herein or the context of their usewould clearly suggest otherwise. “Background Current” is defined hereinas the current that flows in a sensor in the absence of an outsidesignal input such as incident light, and is produced by the inherentcharacteristics of the material property of the diode and also by stressin the sensor. “Affinity Based Binding” is defined herein as binding ofanalyte or analytes to probe or probes that are immobilized on abiosensor's detection surface, which produces signals, e.g., optical,magnetic, electrical, electrochemical, or electro-mechanical, that aredetectable to the biosensor. “Backside” is defined herein as the side ofthe substrate that is opposite to the front side, where the metal stackarchitecture is situated. The terms “biosensor” and “bio-probes” areused to describe the sensor embodiments and the probe embodiments.However, the sensors and probes as described in this disclosure are notlimited to bio-applications. The disclosed sensors and probes alsopertain to other fields of application, including but not limiting toionic, chemical, electrical, mechanical and magnetic applications.

In one or more example embodiments, a CMOS pixel, such as a backsidestimulated biosensor pixel, for sensing at least one selected from abiological, chemical, ionic, electrical, mechanical and magneticstimulus, may include a substrate including a backside. A source may becoupled with the substrate to generate a background current. In oneaspect, the source to generate the background current may include adiode that is substantially disposed within the substrate. A detectionelement, such as a circuit, may be electrically coupled to measure thebackground current. In one or more embodiments, the detection elementmay be a circuit or other element (e.g., readout circuitry) suitable forreading a pixel of a pixel array. The backside surface of the CMOS pixelmay include a layer of probes or bio-probes that affinitively hinds toanalyte. The affinity based binding increases or decreases electricalcharge at or near the backside surface, thereby causing a change in thebackground current or a stimulus. The stimulus, which is to be providedto the backside, may affect a measurable change in the backgroundcurrent. While the term pixel is used herein, it is not required thatthe pixel be used for imaging or even that the pixel detect light orelectrons corresponding to light. Rather, the pixel may have aphotodiode or diode that is used as a source of background current butrather than the photodiode being used as a photodetector the photodiodemay optionally be masked (e.g., with a light or electron blocking layeror material), covered, shielded or otherwise blocked from receivinglight or corresponding electrons so that it need not actually detectlight but may instead be used primarily as a source of backgroundcurrent.

A CMOS “backside” stimulated biosensor pixel is distinguished from a“frontside” stimulated biosensor pixel. A typical CMOS pixel includes asilicon substrate at the bottom, an active device such as a transistorpositioned on the substrate, several metal and dielectric layers abovethe active device. Bio-probes could be positioned on the top surface.The interaction between analytes and bio-probes could produce signalsthat travel through the metal and dielectric layers to the activedevice. The signals could then be measured by the active device andsupporting circuitry so as to quantify the affinity based effects or theamount of interaction between the analytes and the bio-probes. Asignificant drawback of a conventional CMOS pixel architecture is themultiple layers of metals and dielectrics that are stacked on top of theactive device. These multiple interconnect layers are used toelectrically access the transistors, to create a certain circuittopology, and to reduce undesired interaction between a fluidic sampleto be analyzed and the semiconductor structures. However, these multiplelayers also add to the stack height, would increase the bulk of thebiosensor system, and lead to higher system complexity and cost. Thethickness of the stack may also cause a reduction in detectionsensitivity and accuracy. It is desirable to reduce or eliminate theselayers while still allowing access to the transistors and protecting thesemiconductor structures from interaction with the fluidic sample.

Instead of transmitting affinity based binding signals into the CMOSintegrated circuit from the top of the chip through a top metal layer,the signals may be coupled into the CMOS pixel from the bottom andimmediately through the substrate. Instead of being placed on a topmetal layer, the bio-probes may be constructed at the backside of theCMOS pixel on the substrate's backside surface. A backside stimulationscheme has been successfully adopted for CMOS image sensor pixels, suchas OmniVision™ Backside Illumination CMOS imager products. However,prevalent teaching in the CMOS biosensor art suggests that “electricalsignals can only couple from the top and through the pads”, i.e., fromthe front side of the CMOS pixel where the metal/dielectric layers areformed (B. Jang and A. Hassibi, “Biosensor Systems in Standard CMOSProcesses: Fact or Fiction?” Proc. of IEEE International Symposium onIndustrial Electronics (ISIE), 2049, 2008). A backside stimulationscheme challenges this conventional wisdom.

In addition to backside stimulation, for certain biosensor embodiments,rather than using a conventional electrode to measure electrochemicalsignals, such as impedance, potential, current and I-V curves, at theanalyte-electrode interface, embodiments utilize the CMOS pixel'sbackground current as a measurement tool.

In electronic arts, background current is alternatively known as leakagecurrent. It is primarily caused by electronic devices that are attachedto capacitors, such as transistors or diodes, which conduct a smallamount of current even when they are turned off. For a CMOS imagesensor, background current is frequently referred to as dark current. Itis the leakage current at the photodiode node, which discharges thepixel capacitance even though there is no light to stimulate thephotodiode. Background current may be described as having at least twocomponents, ideal background current and stress generated backgroundcurrent.

The ideal background current depends in part on the dopingconcentration, band gap, and the temperature of the photodiode. Theideal background current further includes two sub-components. The firstis an injection-diffusion current due to the injection of thermalelectrons and holes having a higher energy than the built-in potentialenergy of the p-n junction. The second is a generation-recombinationcurrent due to thermal electron-hole generation or recombination withinthe p-n junction. These two components depend on applied voltage andtemperature. The ideal background current is a result of inherentcharacteristics of the material properties of the p-n junction.

The stress generated background current is determined by thecharacteristics of individual defects in the structure of the CMOSpixel. The properties of the material employed in the construction ofthe CMOS pixel and the supporting devices induce background current inthe CMOS pixel through various mechanisms. These mechanisms may includethe following. First, the background current may be produced by ajunction leakage of the photodiode, as well as other leakages throughstructural defects or limitations of the photodiode and its surroundingstructures. Second, the background current may be produced by asub-threshold leakage of the transistors that are connected to thephotodiode. Third, the background current may be produced by adrain-induced-barrier-lowering leakage, or by a gate-induced drainleakage current of the transistors that are connected to the photodiode.

Of particular significance is the leakage current associated with thedepletion region of the photodiode edge and the shallow trench isolation(STI) structure due to the material properties at the interfaces. Forexample, point defects within the sidewalls of the silicon substratethat adjoin the STI structure may generate surface states that functionas leakage paths for electrical charges. Further, dopant ions ingeneral, and boron ions in particular, that are introduced into the STIstructure during ion implantation steps, may affect the surfacepassivation of the silicon substrate that abuts the STI structure. Thesedopant ions may also generate interface charge states that function asleakage paths for electrical charges.

Background current has been described in an empirical model as I=αA+βn,where I, α represents the coefficient that determines the junction unityarea contribution. A represents junction area, β represents thecoefficient that determines the corner contribution, and n representsthe number of corners in the design (Igor Shcherback, Alexander Belenky,and Orly Yadid-Pecht, “Empirical dark current modeling for complementarymetal oxide semiconductor active pixel sensor.” Opt. Eng. 41(6)1216-1219, June 2002). The αA term accounts for the ideal backgroundcurrent component, whereas the accounts for the stress generated leakagecurrent component.

Background current degrades image quality of a CMOS image sensor. Henceits reduction and elimination is an important goal of CMOS image sensorpixel design. Described herein are various embodiments that utilize thenormally undesirable background current as a measurement tool foraffinity binding of a biosensor. Rather than aiming to rid the CMOSpixel of the background current, embodiments described herein maintainan appropriate level of background current, and uses it to detectaffinity based effects at the surface of a CMOS pixel, such as affinitybased binding at a biosensor surface.

For a backside-stimulated CMOS pixel array surface, several sets ofcircumstances on the backside surface affect the CMOS pixel's backgroundcurrent. In one set of circumstances, the presence of electrical chargeon the backside surface affects the background current. In another setof circumstances, mechanical stress on the backside surface affects thebackground current.

The following experimental results suggest that electrical chargepresent on the backside surface affects both the background current andthe image quality of a CMOS image sensor. In a first experiment, thebackside surface contained imperfections of an ionic nature.Accordingly, white spots were present at the sites of imperfection.These white spots had a higher background current value than thesurrounding area. After a stripping process step, the surface chargeimperfections were removed, thereby eliminating the white spots.Accordingly, the former white spots took on a background current valuethat was the same as the surrounding area.

In a second experiment, before application of a voltage to a CMOS imagesensor array's backside surface, background current was observed foreach pixel. Different pixels produced different, but still relativelysimilar background currents. After a positive voltage application, thesurface acquired a positive electrical potential across the board.Accordingly, the background current in different pixels were increasedto a point where the entire backside surface became a “white zone”. Inshort, by applying a uniform voltage bias to the backside of a CMOSimage sensor, defect-free pixels may be made to look like defective,white spot like pixels, so long as a right voltage level is applied.Conversely, by applying a negative voltage bias, defective pixels may bemade to look like defect-free pixels.

These experiments suggest that for a backside-stimulated CMOS pixel,surface charge affects background current behavior. Particularly,positive surface charges increase the background current, whereasnegative surface charges decrease the background current. This principlemay be used to design new types of CMOS sensors that utilize backgroundcurrent as an indicator to measure affinity based effects at thebackside surface. Whereas conventional CMOS sensor systems, such as thebiosensors disclosed in U.S. Patent Application Publications2010/0122904, 2010/0052080, rely on the an active device, such as adiode, to measure input signals of affinity based effects, thebackground current-based sensor system disclosed in the presentapplication cleverly utilizes the CMOS pixel's innate background currentas the basis to measure input signals and affinity based effects. Here,the affinity based effects produce electrical charges at or near thebackside surface. These electrical charges modulate the CMOS pixel'sbackground current.

Apart from electrical charges at or near the backside surface, physicalstress on the backside surface may also affect background current. Asdisclosed in U.S. Patent Application 2010/12708330, covering the surfacewith an extra light shielding layer introduces extra physical stress tothe CMOS pixel that alters the background current. This surface stressaffect on the CMOS pixel's background current may be employed to enablea CMOS biosensor similar to the one discussed immediately above. Here,instead of producing electrical charges at or near the surface, theaffinity based effect produces additional surface stress that in turnaffects the CMOS pixel's background current.

Several backside-stimulated CMOS biosensor systems are disclosed.Bio-probes are immobilized on the CMOS's substrate backside surface. Theaffinity based binding of target analyte and immobilized receptorsproduce signals that are detected by the CMOS pixel. The CMOS pixelutilizes its innate background current to measure the input signals. Oneclass of embodiments relies on affinity based binding to produceelectrical charges at or near the backside surface. An alternate classof embodiments relies on affinity based binding to produce physicalstress on the backside surface.

FIG. 1 illustrates a backside stimulated CMOS biosensor pixel 100, inaccordance with an embodiment. CMOS biosensor pixel 100 includes metalstack 130, interlayer dielectric 120 disposed over metal stack 130, andsubstrate layer 110 disposed over interlayer dielectric 120. The metalstack 130 may include one or more levels of interconnects disposed inone or more dielectric or insulating layers. Substrate layer 110 furtherincludes STI structures 114, diode 111, transfer gate 113, and floatingdiffusion structure 112. The STI structures 114, diode 111, transfergate 113, and floating diffusion structure 112 are substantiallydisposed within the substrate 110. On top of or coupled with backsidesurface 103 are at least one layer of at least one type of immobilizedbio-probes 101. During use, as analyte 102 binds to bio-probes 101, theelectrical charge characteristic at or near backside surface 103changes. Such a change of surface characteristic affects the backgroundcurrent behavior of the CMOS biosensor pixel 100. Accordingly, theaffinity based binding affects the background current. The change inbackground current is detected and processed by the CMOS circuitry. Itis to be appreciated that another embodiment may include an array ofpixels similar to pixel 100.

FIGS. 2A through 2H illustrate several embodiments of affinity basedbinding at or near the backside surface portion of the CMOS biosensorpixel. FIG. 2A shows a positive ion affinity backside surface portion210 that includes a substrate 211 and a negatively charged surface layeror negatively charged entity 212. The negatively charged surface layer212 may include SiO₂, Si₃N₄, Al₂O₃, or Ta/O₅ in a proton-acceptor state.The proton-acceptor state of the negatively charged surface layer 212allows it to bind to positive ion analyte 213 such as proton H+.

FIG. 2B shows a negative ion affinity backside surface portion 220 thatincludes a substrate 221 and a positively charged surface layer orpositively charged entity 222. The positively charged surface layer 222may include SiO₂, Si₃N₄, Al/O₃, or TaO₅ in a hydroxide-acceptor state.The hydroxide-acceptor state of the positively charged surface layer 222allows it to bind to negative ion analyte 223, such as hydroxide OH−.

In some embodiments, the CMOS ion sensors of FIGS. 2A-2B may be operableto sense and/or measure ions (e.g., ion concentrations) in a solution orelectrolyte. In some embodiments, the CMOS sensors may be used to senseor measure hydronium ions (H₃O⁺), such as, for example, to measure thepH of a solution. The pH of a solution represents the negative logarithmof the hydronium ion (H₃O⁺) concentration of the solution. In otherembodiments, the CMOS sensors may be used to measure other types ofions, such as, for example, sodium cations (Na⁺), silver cations (Ag⁺),lead cations (Pb⁺²), cadmium cations (Cd⁺²), chlorine anions (Cl⁻),hydroxide anions (OH⁻), and various other ions known in the arts.Measurement of these various different types of ions have various usesin industry, medicine, science, and otherwise. The CMOS sensorsgenerally tend to offer an advantage of an ability to measure ionconcentration in samples of very small volume. In addition, the arraysof pixels of the CMOS sensors may be used to measure distributions inion concentrations over a two-dimensional area and/or the spatialdistribution in ion concentrations in a very small sample. This may beused for various different purposes in industry, medicine, science, orotherwise. For example, this may be used to measure concentrationgradients, measure diffusivity rates, etc.

FIG. 2C shows a heparin affinity backside surface portion 230 thatincludes substrate 231 and protamine probes 232 that are attached to thesubstrate surface 234. Protamine is a positively charged protein thataffinitively binds to negatively charged heparin 233, which is ananticoagulant, i.e., a blood thinner, that is widely used in medicalprocedures such as renal dialysis, open heart bypass surgery, andtreatment of blood clots. Heparin level should be well controlledbecause heparin overdose leads to dangerous bleeding complications.Affinity based binding between protamine probes 232 and heparin 233 maychange the electric charge characteristics at or near the heparinaffinity backside surface portion 230, which is part of the CMOSbiosensor pixel 100 shown in FIG. 1. Such a change affects backgroundcurrent of the CMOS biosensor pixel 100. In an alternative embodiment,heparin may be used as a bio-probe to detect protamine analyte. In suchan embodiment, the CMOS biosensor system functions as a protaminesensor. Alternatively other positively and negatively charged proteins,or other complementary protein pairs entirely may be used.

FIG. 2D shows a DNA affinity backside surface portion 240 that includessubstrate 241 and DNA probes 242 that are attached to the substratesurface 246. DNA probes 242 are single strand DNA molecules thatcomplementarily bind to analyte, i.e., target DNA 243. As target DNA 243binds to DNA probes 242, the electric charge characteristics of DNAaffinity backside surface portion 240 changes. Such change affects thebackground current of the CMOS biosensor pixel 100 shown in FIG. 1. Toincrease detection sensitivity, target DNA may be modified to producetagged target DNA 244 by attaching label 245 to the target DNA. Label245 amplifies the effect of affinity based binding on the electricalcharacteristics of the CMOS biosensor pixel 100 shown in FIG. 1. Forexample, label 245 may be an electric charge that increases the presenceof electric charge at or near the DNA affinity surface 240. Label 245may also be magnetic in nature, and affects surface characteristicsthrough electromagnetic effects. Label 245 may also be a redox labelsuch as ferrocene, that may either donate or accept electrons.

FIG. 2E shows an antibody-antigen affinity backside surface portion 250that includes substrate 251 and antibody probes 452 that are attached tothe substrate surface 254. As analyte antibody 253 affinitively binds toantibody probes 252, the affinity based binding changes the electriccharge characteristics of the antibody-antigen affinity surface 250. Inthe present embodiment, antibodies are used as bio-probes and antigensare used as analyte. For example, the analyte may be an antigen toxinproduced by an anthrax bacterium, and the bio-probe may be an antibodythat specifically binds to the anthrax antigen. Alternatively, ifanalyte is an antibody, e.g., the HIV antibody in an HIV diagnostictest, then an HIV-specific antigen may be used as a bio-probe that isattached to the antibody-antigen affinity surface 250. Similar to theDNA-related embodiment, the antigen and antibody in theseantigen-antibody embodiments may be tagged with labels in order toincrease detection sensitivity.

FIG. 2F shows an enzyme affinity backside surface portion 260 thatincludes substrate 261 and enzyme probes 262 that are attached to thesubstrate surface 264. By way of example, the enzyme probe may be apenicillinase that converts penicillin into penicilloic acid, a ureasethat converts urea into CO₂ and ammonium, or a glucose oxidase thatconverts glucose into gluconic acid. Examples of the analyte may bepenicillin, urea, or glucose. As analyte 263 binds to enzyme probes 262,the affinity based binding results in an enzymatic reaction that changesthe electric charge characteristics of the enzyme affinity backsidesurface portion 260. For example, the enzymatic reaction may produce areaction product 265 that affects the surface characteristics of theenzyme affinity surface 260. Examples of the reaction product may bepenicilloic acid, CO₂ and ammonium, or gluconic acid.

FIG. 2G shows a cell affinity backside surface portion 270 that includessubstrate 271 and a cell probe 272 that is attached to the substratesurface 274. The cell probe 272 may substantially cover the backsidesurface of a CMOS biosensor pixel 100 as shown in FIG. 1. As analytestimulus 273 impacts the cell probe 272, the resulting reaction changesthe electric charge characteristics of the cell affinity backsidesurface portion 270. For example, the reaction may produce a reactionproduct 275 that affects the surface characteristics of the enzymeaffinity backside surface portion 270. Alternatively, the cell probe 272may be a cardiac cell, a muscular cell, or a neuronal cell that produceselectrical impulses at or near the substrate surface 274.

FIG. 2H shows a tissue affinity backside surface portion 280 thatincludes substrate 281 and tissue probe 282 that are attached to thesubstrate surface 284. The tissue probe 282 may substantially cover thebackside surface of one or several CMOS biosensor pixels. As analytestimulus 283 impacts tissue probe 282, the resulting reaction changesthe electric charge characteristics of the tissue affinity backsidesurface portion 280. For example, the reaction may produce a reactionproduct 285 that affects surface characteristics of the tissue affinitybackside surface portion 280. Alternatively, the tissue probe 282 may bean insect antenna that senses analyte stimulus 283 in the environment.The sensing of analyte stimulus 283 produces electrical impulses at ornear the substrate surface 284.

FIGS. 3A through 3E illustrate several embodiments of manipulating aCMOS pixel's background current so that it may be utilized to measurethe CMOS pixel's surface characteristics. By way of example, thebackground current may have a range of 10 to 100 electrons per second.In one embodiment, the background current may be approximately 50electrons per second. An appropriate background current level allows abackside surface stimulus to produce a relatively high signal to noiseratio, which is desirable for detection sensitivity.

In one set of circumstances, the geometry of a diode in the CMOS pixelis manipulated or different than typical (e.g., not cubic) to generate adesirable level of background current. In another set of circumstances,the STI structure is manipulated or different than typical (e.g.,rougher or different doping than adjacent areas) to generate a desirablelevel of background current. Yet in another set of circumstances, thebackground current is dynamically controlled.

FIG. 3A is a perspective view that shows a CMOS pixel 310 that containssubstrate 313, a diode 311 and an STI structure 312 inside the CMOSpixel 310. Neither the diode 311 nor the STI structure 312 has beenmanipulated. The geometry of the diode 311 is cuboid (e.g., cubic orrectangular solid). That is the planar cross section is rectangular orsquare.

FIG. 3B is a perspective view that shows a CMOS pixel 320 that containsa manipulated diode 321. By way of example, the manipulated diode has across sectional geometry that resembles a hexagon. The overall shape ishexagonal solid. This geometry is different from the unmanipulatedcuboid diode 311 as shown in FIG. 3A, whose cross sectional geometryresembles a rectangle or square. A hexagon shaped diode may produce abackground current that is different from the background currentproduced by a cuboid diode. Several factors may cause the hexagon shapeddiode to produce a different background current from the rectangulardiode. An example of such factors may be that the hexagon shaped diodehas more corners and/or angles. Other shapes besides hexagonal arepossible, such as having cross sectional shapes with more than foursides. In one or more embodiments, a diode may have more vertical sidesor more corners than a cubic or rectangular solid. In one or moreembodiments, a diode 321 may have either more angles than a cuboid orless angles than a cuboid.

In one or more embodiments, the source to generate the backgroundcurrent may include a shallow trench isolation (STI) structure that issubstantially disposed within the substrate. In one or more embodiments,the STI structure of the CMOS biosensor pixel is manipulated ordifferent than typical (e.g., rougher than a typical STI structure orlighter doping profile around it) for the same purpose.

FIG. 3C is a cross sectional view that shows a CMOS pixel 330 thatcontains a manipulated STI structure 332. By way of example, themanipulated STI structure 332 contains one or more edges that arerougher than an unmanipulated STI structure. The relative roughness ofthe edges causes a different amount of stress from smooth edges,resulting in a different level of background current.

FIG. 3D is a cross sectional view that shows a CMOS pixel 340 thatcontains dopant 345. By way of example, dopant 345 may include boronions. Dopant 345 may be around the STI structure 342. Dopant 345 mayhave a higher concentration range, or a lower concentration rangecompared to regions farther away from the STI. An example of the dopantconcentration range may be approximately 1014 to 1016 ions per cm3.Another example of the dopant concentration range may be approximately1017 to 1020 ions per cm3. The presence of dopant 345 that issubstantially within a predetermined concentration range affects thesurface passivation of the part of substrate 343 that abut the STIstructure 342, and generates interface charge states that function asleakage paths for electrical charges, thereby affecting backgroundcurrent of the CMOS pixel 340.

FIG. 3E is a cross sectional view that shows a CMOS pixel 350 thatcontains substrate 353, a diode 351 and an STI structure 352. Aninductive coil 354 or other heater or heating element such as aresistive heater is positioned in the vicinity of or proximate the CMOSpixel 350, for example coupled with the substrate 353. The inductivecoil 354 may be manipulated in order to affect the temperature of theCMOS pixel 350. As used herein the inductive coil is in the vicinity ofor proximate the CMOS pixel if it is located sufficiently to affect thetemperature of the CMOS pixel. By way of example, an electric currentmay be passed through the inductive coil 354 to heat it. The inductivecoil 354 may serve as a temperature reference. The heating of theinductive coil 354 may affect the temperature of the CMOS pixel 350. Achange of temperature in the CMOS pixel 350 affects its backgroundcurrent.

FIG. 3F is a cross sectional view that shows an inductive coil 364 thatis positioned in the vicinity of a CMOS pixel 360. A temperature sensor366 is coupled to both a reference pixel 365 and the inductive coil 364so that the inductive coil 364 controls the temperature of the CMOSpixel 360 relative to the reference pixel 365. The reference pixel, thetemperature sensor, and the inductive member may form a feedbackmechanism to control a temperature of the CMOS pixel.

FIG. 4A is a cross sectional view that shows a CMOS pixel array 400 thatincludes a multitude of CMOS pixels 402, 403 and 404. The CMOS pixelarray 400 includes a backside surface layer 401 that may sense thepresence of electrical charges. Since each individual CMOS pixel candetect electrical charge or charges above it, the array of CMOS pixelsmay detect the movement of electrical charge or charges. Movementdetection of charged entities may be used to measure the properties ofthese charged entities such as their mass, size, shape, or orientation.

In one or more embodiments, a biosensor system may include a backside ofa substrate, an array of CMOS pixels underneath the backside of thesubstrate, and a multitude of bump structures coupled with the backsideof the substrate. As used herein, a multitude includes at least 20, insome cases at least 50, in some cases at least 100, or more. Themultitude of bump structures may be substantially separated by voids.

FIG. 4B is a cross sectional view that shows a modified backside surfaceportion 410 of the CMOS pixel array 400 as disclosed in FIG. 4A. Themodified backside surface layer 410 includes a substrate 411, and bumpstructures 412, 413 and 414 that are situated on surface 415. The bumpstructures 412, 413 and 414 may form cavities 416 and 417 between them.The bump structures and the cavities may assist the measurement of theflow of particles, electrical charges and other entities on the surface415. By way of example, the bump structures and the cavities may bearranged to form channels that may direct the flow of particles,electrical charges and other entities. In another example, the cavitiesmay be of different sizes, thereby allowing the separation and sortingof particles, electrical charges and other entities.

In another set of embodiments, a cantilever structure is constructed ontop of the backside surface of a CMOS biosensor pixel. Bio-probes areattached to the cantilever structure. Affinity based binding betweenanalyte and the bio-probes affect the stress condition of the CMOSpixel's backside surface, thereby causing a change in the backgroundcurrent.

FIG. 5 illustrates a backside stimulated CMOS biosensor pixel 500, inaccordance with an embodiment. Aside from differences specificallymentioned, the pixel 500 may be similar to and/or have features of thepixel 100 of FIG. 1. For brevity, these features will not beunnecessarily repeated. CMOS biosensor pixel 500 includes metal stack530, interlayer dielectric 520, and substrate layer 510. Substrate layer510 further includes STI structures 514, diode 511, transfer gate 513,and floating diffusion member 512. On top of the CMOS backside surface503 is a cantilever 504. In one embodiment, the cantilever 504 issubstantially situated on or coupled with the CMOS backside surface 503.Cantilever 504 includes a detection surface 505, onto which bio-probes501 are immobilized or coupled. Analyte 502 may bind to bio-probes 501,thereby adding mass to the cantilever 504. Accordingly, the stress onthe CMOS backside surface 503 changes. Such change of surface stressaffects the background current behavior of the CMOS biosensor pixel 500.The changes in the background current is detected and processed by theCMOS circuitry.

Cantilever 504 may have different modes of operation. By way of example,cantilever 504 may have a static mode of operation. In the static mode,affinity based binding of analyte 502 to bio-probes 501 causes a staticbending of the cantilever 504. The static bending changes the surfacestress of the CMOS backside surface 503, thereby causing a detectablechange in the background current of the CMOS biosensor pixel 500.

In another example, cantilever 504 may have a dynamic mode of operation.In the dynamic mode, cantilever 504 may be mechanically excitedsubstantially at its resonant frequency. The mechanical excitation maybe produced by various forces. By way of example, one mechanicalexcitation force may be a piezoelectric force. The mechanical excitationof cantilever 504 may cause dynamic stress cycles on the CMOS backsidesurface 503. Affinity based binding of analyte 502 to bio-probes 501 mayadd additional mass to the cantilever 504, causing a shift in theresonant frequency. The shift of resonant frequency may cause acorresponding frequency shift of dynamic stress cycles on the CMOSbackside surface 503, which is detectable by monitoring the backgroundcurrent of the CMOS biosensor pixel 500. An alternate embodiment mayinclude an array of cantilevers with each cantilever corresponding to apixel in a corresponding array of pixels.

FIGS. 6A through 6C illustrate several embodiments of coupling betweenthe cantilever and the CMOS backside surface in additional to FIG. 5.FIG. 6A shows a cantilever 610 having a cantilever arm 611. Bio-probes612 are attached to a cantilever arm surface 614. The cantilever arm 611is substantially coupled to a CMOS backside surface 616 through anintermediate member 615. By way of example, as analyte 633 may bind tobio-probes 612, the cantilever arm 611 bends. The resulting stress maybe transferred to the CMOS backside surface 616 through the intermediatemember 615. The intermediate member 615 may be various convenientmaterials. In another example, the cantilever arm 611 may bemechanically excited, resulting in cyclic motion of the cantilever arm611. The resulting stress cycles may be transferred to the CMOS backsidesurface 616 through the intermediate member 615.

FIG. 6B shows a cantilever 620 having a cantilever arm 612. Bio-probes622 are attached to a cantilever arm surface 624. The bio-probes 622 maybe affinitively bound to analyte 623. The cantilever arm 621 may becoupled to a CMOS backside surface 626 through a tip member 625. The tipmember 625 may transfer stress and motion of the cantilever arm 621 tothe CMOS backside surface 626. Similar to the embodiment disclosed inthe previous paragraph, the present embodiment may have several modes ofoperation, including a static mode and a dynamic mode.

FIG. 6C shows a cantilever 630 having a cantilever arm 632. Thecantilever 630 includes a base portion 637. The cantilever 630 may besubstantially situated on a CMOS backside surface 636, with the baseportion 637 substantially situated onto a notch-like structure 638 thatis within the CMOS backside surface 636. The interaction between thebase portion 637 and the notch-like structure 638 may facilitate thetransfer of stress between the cantilever 630 and the CMOS backsidesurface 636. Bio-probes 632 may be attached to a cantilever arm surface634. The bio-probes 632 may be affinitively bound to analyte 633. Theaffinity based binding adds to the mass of the cantilever 630. In astatic mode of operation, the added mass affects the stress on the CMOSbackside surface 636. In a dynamic mode of operation, the added massaffects the frequency of cyclic stress of the CMOS backside surface 636.

FIG. 7 is a block diagram illustrating a CMOS biosensor 700, inaccordance with an embodiment. The illustrated embodiment of the CMOSbiosensor 700 includes pixel array 702. The pixel array 702 or theindividual CMOS pixels 701 making up the pixel array 702 may have someor all of the above described characteristics. The CMOS biosensor 700also includes at least a readout circuitry 710, a function logic 715,and a control circuitry 720. The readout circuitry 710 represents anexample embodiment of a detection element to measure the backgroundcurrent. Pixel array 702 may be a two-dimensional array of individualCMOS pixels 701 (e.g., pixels P1, P2 . . . , Pn). As illustrated, eachindividual pixel 701 is arranged into a row (e.g., rows R1 to Ry) and acolumn (e.g., column C1 to Cx) to acquire data of an affinity basedbinding between an analyte and a bio-probe. These data can then be usedto render a two-dimensional data set of analyte information. Forexample, each individual pixel may be used to detect a particular DNAsequence. An array of different pixels may allow a simultaneousdetection of various DNA sequences that make up an entire genome, whichis an ensemble of these various DNA sequences. In short, the CMOSbiosensor 700 permits the determination of DNA sequence information ofan entire genome in one measurement.

After each pixel 701 has acquired its data, the data is readout by thereadout circuitry 710 and transferred to the function logic 715. By wayof example, the readout circuitry 710 may include at least anamplification circuitry, an analog-to-digital conversion circuitry, orotherwise. The function logic 715 may simply store the data or evenmanipulate the data by applying post measurement effects. In oneembodiment, readout circuitry 710 may readout a row of data at a timealong readout column lines (illustrated) or may readout the data using avariety of other techniques (not illustrated), such as a column/rowreadout, a serial readout, or a full parallel readout of all pixelssimultaneously. Control circuitry 720 is connected with the pixel array702 to control operational characteristic of some or all of the pixels701 that make up the pixel array 702. For example, control circuitry 720may generate a signal or signals to alter the background current in someor all of the pixels 701 so as to improve the detection sensitivity of aparticular affinity based binding bio-assay.

In some embodiments, for example when CMOS biosensor 700 is used as anion sensor, a reference electrode 703 may optional be included. Duringuse, the reference electrode 703 may be inserted into a sample (e.g., anelectrolyte or solution under test). In some embodiments, the referenceelectrode may represent an electrode with a relatively stable andrelatively well-known electrode potential. The reference electrode mayhelp to stabilize the potential of the electrolyte and/or keep thepotential of the electrolyte substantially constant. By substantiallyconstant it is meant more constant than would be expected without thereference electrode but allowing for the possibility of generally smallfluctuations that tend to occur despite attempts to maintain constantlevels using the reference electrode. As shown, in some embodiments, thereference electrode 703 may include a voltage reference VREF.Alternatively, a current reference may optionally be used instead. Insome cases, the reference electrode 703 may be relatively simple, forexample, a plate electrode, a parallel plate, adjacent plates, etc. Amore sophisticated electrode assembly may optionally be used, ifdesired. In various embodiments, any of the reference electrodes shownand described in any of FIGS. 9, 10, and 11 may optionally be used.

FIG. 8 is a circuit diagram illustrating a pixel circuitry 800 of twofour-transistor pixels within a pixel array, in accordance with anembodiment of the disclosure. Pixel circuitry 800 is one possible pixelcircuitry architecture for implementing each pixel within pixel array702 of FIG. 7. However, it should be appreciated that embodiments arenot limited to four-transistor pixel architectures; rather, one ofordinary skill in the art having the benefit of the instant disclosurewill understand that the present teachings are also applicable tothree-transistor designs, five-transistor designs, and various otherpixel architectures.

In FIG. 8, pixels Pa and Pb are arranged in two rows and one column. Theillustrated embodiment of each pixel circuitry 800 includes a diode DD,a transfer transistor T1, a reset transistor T2, a source-follower(“SF”) transistor T3, and a select transistor T4. During operation,affinity based binding between analytes and bio-probes may modulate thelevel of a background current in pixels Pa and Pb. Further, diode DD mayhave an interface with its surrounding substrate, wherein the interfacemay be a primary source of the background current. Transfer transistorT1 receives a transfer signal TX, which transfers the background currentfrom the vicinity region of diode DD to a floating diffusion node FD. Inone embodiment, floating diffusion node FD may be coupled to a storagecapacitor for temporarily storing charges from the background current.

Reset transistor T2 is coupled between a power rail VDD and the floatingdiffusion node FD to reset the pixel (e.g., discharge or charge the FDand the DD to a preset voltage) under control of a reset signal RST. Thefloating diffusion node FD is coupled to control the gate of SFtransistor T3. SF transistor T3 is coupled between the power rail VDDand select transistor T4. SF transistor T3 operates as a source-followerproviding a high impedance connection to the floating diffusion FD.Finally, select transistor T4 selectively couples the output of pixelcircuitry 800 to the readout column line under control of a selectsignal SEL.

In some embodiments, for example when the pixel circuitry 800 is used asan ion sensor, each of the pixels may optional include a referenceelectrode 803. During use, each reference electrode may participateelectrically with its corresponding pixel via an electrical connectionthrough an electrolyte or solution when the pixels are employed as partof an ion sensor system. The reference electrodes may participate in theion sensing action when pixels are employed as ion sensor pixels. Asshown, in some embodiments, each reference electrode 803 may include avoltage reference VREF. Alternatively, current reference electrodes orother electrical reference element may optionally be used instead.

FIG. 9 is a cross sectional view of a CMOS ion sensor system with areference electrode 540 proximate to its backside surface, in accordancewith an embodiment. Certain features shown in FIG. 9 are similar tothose shown in FIG. 5 (except for the cantilever 504 and immobilizedbio-probes 501). However, in FIG. 9, a surface at the backside isexposed to an electrolyte, solution, or other sample 570, with thereference electrode 540 inserted into the sample. The referenceelectrode 540 is inserted in the electrolyte to help keep the potentialof electrolyte substantially constant. In some embodiments, thereference electrode 540 may be biased at a voltage. In variousembodiments, the reference electrode 540 may represent a pin, probe,plate, member, or other structure. FIG. 9 also shows optional dielectriclayer 550 formed on the surface at the backside of substrate 510.Depending on whether reference electrode 540 is a voltage referenceelectrode or a current reference electrode, and depending on thephysical location of reference electrode 540, the incorporation ofdielectric layer 550 may be desirable, but is not required. Dielectriclayer 550 may be optically opaque or transparent, and may consist ofeither a single layer or multiple layers.

FIG. 10 is a cross sectional view of a CMOS ion sensor system having areference electrode 560 on its backside surface, in accordance with anembodiment. FIG. 10 shows reference electrode 560 formed on at least aportion of a surface at the backside of the substrate. In this case, thereference electrode 560 is formed over (in this case directly on)dielectric layer 550. In the illustration, the dielectric layer 550 isdisposed or sandwiched between the reference electrode 560 and thesubstrate 510, although one or more other layers may optionally bedisposed therebetween as well. The dielectric layer 550 may be able toinsulate the metallic or otherwise conductive reference electrode fromsensor substrate 510. In the illustrated embodiment, the dielectriclayer 550 is formed substantially over the entire backside surface,including under the reference electrode 560 and at an intended locationwhere a sample 570 is to be contacted, although this is not required. Inother embodiments, the dielectric layer 550 may be formed only underreference electrodes 560 but not over part of the substrate 510 wherethe sample 570 is to be contacted. This may allow the sample 570 tocontact the backside surface of substrate 510 directly, which in somecases may help to improve ion detection. A method of an embodiment mayinclude patterning (e.g., lithographically patterning) the referenceelectrode 560 and optionally the dielectric layer 550.

FIG. 11 is a cross sectional view of a CMOS ion sensor system having areference electrode 580 opposite its backside surface, in accordancewith an embodiment. Reference electrode 580 is positioned proximate tosubstrate 510 with electrolyte 570 disposed there between. In someembodiments, reference electrode 580 may be a single electrode plateextending over substantially all the pixels in the array of pixels. Forexample, the reference electrode 580 may occupy a plane substantiallyparallel to the surface at the backside and may be displaced from thesurface at the backside to allow introduction of the electrolyte into aspace between the surface at the backside and the reference electrode.Alternatively, reference electrode 580 may include an array of electrodeplates with positioned above corresponding pixels or sets of pixels. Forexample, there may be a first reference electrode portion over one pixeland a second reference electrode portion over another pixel. Referenceelectrode 580 may be biased with a voltage, or comprise a currentsource, or other electrical reference useful to the operation of ionsensor pixel 500. In the illustrated embodiment, optional dielectriclayer 550 is shown to be formed only partially covering the backsidesurface of substrate 510 (e.g., outside of and peripherally surroundinga contact region for sample 570). In another embodiment, dielectriclayer 550 may optionally be formed over the entire backside surface ofsubstrate 510. In still other embodiments, the dielectric layer 550 mayoptionally be omitted entirely from the backside surface of substrate510.

The CMOS ion sensors of FIGS. 9-11 may be able to sense or measure ionsin samples. In some embodiments, the ions in the samples may affect ameasurable effect on a background current which is measurable by theCMOS ion sensors. In some embodiments, the measurable effect may berelated to a concentration or amount of the ions in the samples. TheCMOS ion sensors may be used to measure concentrations or amounts of theions in the samples. In some embodiments, the CMOS ion sensors mayrepresent CMOS hydronium ion sensors that are operable to sense ormeasure hydronium ions, or concentrations of hydronium ions, in thesamples. In some embodiments, the effect on the backround current of thehydronium ions may be used to measure a pH of the samples. Otherembodiments are not limited to hydronium ions but rather may be used tosense or measure various other ions known in the arts.

The CMOS ion sensors in FIGS. 9-11 may also included various otheraspects disclosed elsewhere herein. In some embodiments, the CMOS ionsensors may incorporate the features or characteristics of the ionsensors of FIGS. 2A-2B. The various detection systems and circuitsdisclosed herein for detecting the changes in the background current, orothers that will be apparent to those skilled in the art, are generallysuitable. For example, transistors and circuitry as described for FIG. 8may be leveraged. The various sources of background current mentionedelsewhere herein, or others that will be apparent to those skilled inthe art, are generally suitable for these ion sensors. For example, thesources of FIGS. 3B, 3C, 3D, 3E, and 3F may optionally be used. Also,the features of FIGS. 4A-4B may optionally be used for the ion sensors,if desired. In some embodiments, at least one of a blocking layer and ablocking material may be included to block light from pixels.

The above description of illustrated embodiments of the invention,including what is described in the Abstract, is not intended to beexhaustive or to limit the invention to the precise forms disclosed.While specific embodiments of, and examples for, the invention aredescribed herein for illustrative purposes, various modifications arepossible within the scope of the invention, as those skilled in therelevant art will recognize.

These modifications can be made to the invention in light of the abovedetailed description. The terms used in the following claims should notbe construed to limit the invention to the specific embodimentsdisclosed in the specification. Rather, the scope of the invention is tobe determined entirely by the following claims, which are to beconstrued in accordance with established doctrines of claiminterpretation.

In the above description and in the claims, the term “coupled” may meanthat two or more elements are in direct physical or electrical contact.However, “coupled” may instead mean that two or more elements are not indirect contact with each other, but yet still co-operate or interactwith each other, such as, for example, through one or more interveningcomponents or structures.

In the description above, for the purposes of explanation, numerousspecific details have been set forth in order to provide a thoroughunderstanding of the embodiments of the invention. It will be apparenthowever, to one skilled in the art, that other embodiments may bepracticed without some of these specific details. The particularembodiments described are not provided to limit the invention but toillustrate it. The scope of the invention is not to be determined by thespecific examples provided above but only by the claims below. In otherinstances, well-known circuits, structures, devices, and operations havebeen shown in block diagram form or without detail in order to avoidobscuring the understanding of the description.

Reference throughout this specification to “one embodiment”, “anembodiment”, or “one or more embodiments”, for example, means that aparticular feature may be included in the practice of the invention.Similarly, in the description various features are sometimes groupedtogether in a single embodiment, figure, or description thereof, for thepurpose of streamlining the disclosure and aiding in the understandingof various inventive aspects. This method of disclosure, however, is notto be interpreted as reflecting an intention that the invention requiresmore features than are expressly recited in each claim. Rather, as thefollowing claims reflect, inventive aspects may lie in less than allfeatures of a single disclosed embodiment. Thus, the claims followingthe Detailed Description are hereby expressly incorporated into thisDetailed Description, with each claim standing on its own as a separateembodiment of the invention.

1-21. (canceled)
 22. A CMOS (Complementary Metal Oxide Semiconductor)pixel to sense at least one stimulus selected from a biological,chemical, ionic, electrical, mechanical and magnetic stimulus,comprising: a substrate including a backside; a source coupled with thesubstrate to generate a background current; a first diode, and adetection system electrically coupled with the substrate to measure aneffect on the background current; at least one charge sensitive layerhaving an elect cal charge and that is coupled with the backside,wherein the at least one charge sensitive layer is to interact with ananalyte that is to be exposed to the at least one charge sensitivelayer, and wherein interaction of the at least one charge sensitivelayer with the analyte is to provide a non-light emitting stimulus thatis to alter the electrical charge of the at least one charge sensitivelayer and is to affect the measurable effect on the background currentwhich is measurable by the detection system; and a reference electrodeproximate to the backside of the substrate.
 23. The CMOS pixel of claim22, wherein the detection system includes at least one of a diode, atransfer transistor, a reset transistor, a floating diffusion node, asource follower transistor, and a select transistor.
 24. The CMOS pixelof claim 23, wherein the transfer transistor and the reset transistoract to reset the first diode to a voltage level that is in partdetermined by the effect of the stimulus on the background current. 25.The CMOS pixel of claim 23, wherein the transfer transistor, thefloating diffusion node, and the source follower transistor are to readout a voltage level from the first diode that is in part determined bythe effect of the stimulus on the background current.
 26. The CMOS pixelof claim 22, wherein the at least one charge sensitive layer is aninsulating layer.
 27. The CMOS pixel of claim 22, wherein the at leastone charge sensitive layer is within the substrate and is of a samematerial as the substrate and is adjacent to the backside of thesubstrate.
 28. The CMOS pixel of claim 22, wherein the at least onecharge sensitive layer has a capacity of affinity based modification ofa charge of the first diode, and wherein the affinity based modificationof the charge of the first diode affects a measurable change in aneffect of the background current.
 29. The CMOS pixel of claim 22,wherein the source to generate the background current includes a seconddiode that is substantially disposed within the substrate.
 30. The CMOSpixel of claim 22, wherein the source to generate the background currentincludes a shallow trench isolation structure that is substantiallydisposed within the substrate, and wherein at least one of: (1) theshallow trench isolation structure includes at least one rough surface;and (2) the substrate includes a portion adjacent to the shallow trenchisolation structure that includes embedded dopant atoms.
 31. The CMOSpixel of claim 30, wherein the embedded dopant atoms include boron ions.32. The CMOS pixel of claim 22, wherein the analyte comprises ionswithin an electrolyte, and wherein a concentration of the ions in theelectrolyte is to affect the measurable effect on the background currentwhich is measurable by the detection system.
 33. The CMOS pixel of claim32, wherein the ions comprise hydronium ions, and wherein the effect onthe background current is to be used to measure a pH of the electrolyte.34. The CMOS pixel of claim 22, wherein the reference electrode isformed on at least a portion of a surface at the backside of thesubstrate.
 35. The CMOS pixel of claim 22, wherein the referenceelectrode is formed on a dielectric layer, and wherein the dielectriclayer is disposed between the reference electrode and the backside ofthe substrate.
 36. The CMOS pixel of claim 22, wherein the referenceelectrode comprises one of a voltage reference and a current reference.37. The CMOS pixel of claim 22, wherein the reference electrodecomprises a first reference electrode portion over the pixel and asecond reference electrode portion over a second pixel.
 38. The CMOSpixel of claim 22, further comprising at least one of a blocking layerand a blocking material to block light from the pixel.
 39. An ion sensorcomprising: a substrate having a frontside and a backside opposite thefrontside, the frontside having a metal stack over Complementary MetalOxide Semiconductor (CMOS) circuitry; at least one of a diode and astructure, which is disposed within the substrate, and which is operableto generate a background current; a circuit electrically coupled withthe substrate and operable to measure the background current; anelectrical charge located at the backside of the substrate, theelectrical charge having a magnitude and to be coupled with an ioniccharge magnitude of an electrolyte that is to be disposed on a surfaceat the backside of the substrate, wherein the coupling of the electricalcharge with the electrolyte, without a need for light emission, is tocause a change in the background current that is to be measured by thecircuit; and a reference electrode proximate to the backside.
 40. Theion sensor of claim 39, wherein the reference electrode occupies a planesubstantially parallel to the surface at the backside and is displacedfrom the surface at the backside to allow introduction of theelectrolyte.
 41. The ion sensor of claim 39, wherein the referenceelectrode is formed on at least a portion of a surface at the backsideof the substrate.
 42. The ion sensor of claim 39, further comprising atleast one of a blocking layer and a blocking material to block lightfrom a pixel corresponding to the circuit.
 43. An ion sensor systemcomprising a substrate having a backside; and an array of CMOS(Complementary Metal Oxide Semiconductor) pixels disposed within thesubstrate; a charge affinity layer coupled with the backside of thesubstrate; and a reference electrode positioned to contact anelectrolyte test sample disposed between the reference electrode and thebackside of the substrate.
 44. The ion sensor system of claim 43,wherein the reference electrode is one of a voltage reference and acurrent reference.
 45. The ion sensor system of claim 43, wherein theion sensor system comprises a hydronium ion sensor system.